Allergic asthma is a disease that impacts the lives of millions in the US and across the world. Many clinical, environmental, biologic, and genetic factors intersect to create this disease. Allergen exposure is critical to the development of allergic asthma. One allergen central to the development of allergic asthma, especially in children, is Alternaria, a common mold. A critical feature of Alternaria differentiating it from more benign allergens is protease activity. Allergen proteases provide mechanisms for increased allergen biological activity such as disrupting epithelial cell tight junctions and directly activating, solubilizing, or degrading cell surface receptors. There are endogenous inhibitors of proteases, including SERine Protease INhibitors (Serpins) and Stefin protease inhibitors, which are differentially upregulated with Alternaria exposure. The Central Hypothesis of this application is that Alternaria proteases are essential to Alternaria acting as an asthmagen by directly target the epithelium and that Alternaria-induced host antiproteases can modulate these effects. We will utilize proteomics, in vitro assays, and a murine model of Alternaria induced lung inflammation to assess the interaction of the epithelium and host antiproteases with Alternaria proteases and determine their impact on the development of allergic asthma. PUBLIC HEALTH RELEVANCE: Alternaria is a protease containing allergic pathogen central to the development of allergic asthma. This application investigates the interaction of Alternaria proteases with the host protease defenses in the pathogenesis of asthma. The results may lead to both primary prevention of asthma and novel asthma treatment options.